The influenza A virus represents one of the greatest global human health risks. While vaccines provide significant protection from seasonal flu infections they still account for an estimated 36,000 deaths and 200,000 hospitalizations per year in the US alone. Furthermore, the inherent time involved in development, production and distribution of vaccines limits their potential efficacy against rapidly emerging outbreaks. Two classes of drugs have been approved for influenza prophylaxis and treatment. Alarmingly, the past decade has witnessed the emergence of drug resistant as well as novel 2009 pandemic (H1N1) and highly pathogenic (H5N1) strains of influenza A. Amantadine- resistance has become so widespread the amantadanes have become all but ineffective and some flu strains have already exhibited significant resistance to neuraminidase inhibitors. Optimally, as adopted for the treatment of other viral diseases, combination drug therapies would be used to provide the most effective prophylaxis and treatment and to inhibit the emergence of additional drug- resistances. Thus, there is an urgent need for new and more effective antiviral mono- and combination therapies. Here we provide an innovative approach to identify inhibitors of both amantadine-sensitive and -resistant forms of the M2 proton channel to provide novel broad-spectrum therapeutics. Using this approach we provide a platform for the identification of new inhibitory compounds acting at novel sites of a clinically validated influenza A target for the development of new mono- and combination antiviral drug therapies; a designated NIAID high priority area of interest.